A deep look into acetylcholinesterase phosphonylation by organophosphate pesticides: A computational study

Abstract

Acetylcholinesterase (AChE) is one of the important enzymes located in the central and peripheral nervous system of organisms. The primary physiological function of AChE is to regulate the concentration of the neurotransmitter acetylcholine (ACh) by a process of hydrolyzing ACh into acetyl and choline. This natural AChE receptor ACh regulatory mechanism can be disrupted by an array of several other compounds that have different chemical and structural characteristics. Our main focus is on inhibition of AChE by organophosphate (OP) compounds. We have disclosed several different potential mechanisms of OP and AChE in a previous study (Rathnayake and Northrup, 2016). In this extended study, we have performed protein and ligand docking, and molecular dynamic (MD) calculations to validate the reaction mechanisms in our previous study and to find the important parameters and behavioral activities of OPs in their targeted biological system AChE. To achieve these goals, we have conducted docking and MD simulations on ten OP compounds with AChE. Our results show that, depending on the size of the OPs, they tend to interact in two distinct locations in the active site of AChE. Acute OP poisoning may be happening in the reaction site that is in the deepest part of the active site by relatively smaller OP compounds, while less potent OP poisoning can be predicted by relatively larger OP compounds in the other reaction site. Further analysis is still underway to characterize additional activities of OPs on AChE.